Melphalan, chemically known as 4-[bis(2-chloroethyl)amino]-L-phenylalanine and also by other names like L-phenylalanine mustard, L-sarcolysine or L-PAM is a bi-functional alkylating agent that acts against selected human neoplastic diseases and is the L-isomer of 4-[bis(2-chloroethyl)amino]-phenylalanine, which exhibits superior anti-tumor activity than medphalan (D-isomer) and sarcolysine (DL-isomer). Melphalan is marketed as its hydrochloride salt, under the brand name ‘Alkeran®’ by The Wellcome Foundation.
Various researchers have attempted to synthesize the active hydrochloride salt of the L-form of 4-[bis(2-chloroethyl)amino]-phenylalanine. The synthesis of melphalan was first disclosed in U.S. Pat. No. 3,032,584 and U.S. Pat. No. 3,032,585 wherein melphalan free base is prepared by a synthetic route which employs a phthalimide functional group for protecting the glycine amino functional group. However, these and the subsequent patents GB 1,377,336 and EP 233 733, do not disclose a method for isolating the acid addition salts of the L-form of 4-[bis(2-chloroethyl)-amino]-phenylalanine, specifically the hydrochloride salt.
U.S. Pat. No. 4,997,651 discloses a method for preparing melphalan hydrochloride comprising addition of hydrochloric acid to a slurry of melphalan free base in an alcohol, preferably ethanol and refluxing the mixture for minimum duration to reduce the level of impurities. The present inventors have noted that complete conversion of the free base to the hydrochloride salt in a short time on a commercial scale is not practically feasible because it results in large amounts of unreacted material. Further, an extended duration of heating in alcohols was found to result in associated impurities, which required successive purifications for obtaining a product of the desired purity. Also, an additional purification step reduces the yield considerably, thereby limiting the suitability of the method to laboratory scale preparation only.
Similarly, GB 1,064,972, FR 1 360 836 and DE 1 292660 also describe the use of an alcohol for preparing the hydrochloride salt with the same disadvantages. RO 57195 describes a method for purification of melphalan free base through formation of the hydrochloride salt followed by treatment with a suitable base such as sodium bicarbonate or sodium acetate. The document is silent about isolation of hydrochloride salt. However, if one carries out the isolation, one would face the problem of associated impurities, which eventually requires extensive purification.
U.S. Pat. No. 4,997,651 and DE 1 292660 also utilize an alcoholic solution of hydrochloric acid with the same result. A replication of these prior art methods by the present inventors revealed that associated impurities were formed, thus requiring subsequent purifications. Regulatory guidelines necessitate the removal of associated impurities by purification to obtain melphalan hydrochloride of desired purity, which eventually reduces the yield.
It is clearly evident from the above prior art that the product obtained by prior art methods generate associated impurities of up to 5-8% and requires extensive purification resulting in high production cost and thereby making such process commercially unsuitable. Moreover, health authorities all over the world have very stringent norms for permissible limits of associated impurities in the final dosage formulation.
Therefore, to overcome the problems associated with prior art, there was a need to develop                i) a simple, efficient, high yielding process which does not result in unreacted starting material remaining after treatment with hydrochloric acid and        ii) a process which yields a product of desired purity with minimal impurities, thereby obviating the need for extensive purification.        